Metabolic Syndrome Under Fire

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Can J Cardiol Vol 22 No 5 April 2006 379

Metabolic syndrome under fire:Weighing in on the truth

Alice YY Cheng MD FRCPC

1

, Lawrence A Leiter MD FRCPC FACP

1,2

Section Editor: Subodh Verma MD PhD

1Division of Endocrinology and Metabolism, St Michael’s Hospital, Toronto; 2Credit Valley Hospital, Mississauga, OntarioCorrespondence: Dr Lawrence A Leiter, Division of Endocrinology and Metabolism, St Michael’s Hospital, University of Toronto,

61 Queen Street, Toronto, Ontario M5C 2T2. Telephone 416-867-7447, fax 416-867-3696, e-mail [email protected]

Received for publication November 28, 2005. Accepted December 8, 2005

CLINICAL CONTEXTThe metabolic syndrome is typically described as a constella-tion of metabolic abnormalities associated with an increasedrisk of cardiovascular disease (CVD) and type II diabetes mel-litus (DM) (1). Over the past two decades, many other names

have been given for this constellation, including ‘insulin resist-ance syndrome’, ‘syndrome X’ and ‘the deadly quartet’. Therehas also been an abundance of differing diagnostic criteria thathave been developed by various organizations around theworld. To add to the confusion, a recent joint statement fromthe American Diabetes Association (ADA) and the EuropeanAssociation for the Study of Diabetes (EASD) has called intoquestion the existence and validity of the metabolic syndromeas a discrete clinical entity (2). In an attempt to shed somelight on the situation, the present article describes the historical

background, reviews the most commonly used clinical criteria,discusses the controversy surrounding the existence of themetabolic syndrome and concludes with the authors’ view-points on the syndrome’s clinical utility.

HISTORICAL BACKGROUNDThe metabolic syndrome, like many things in medicine, repre-sents a ‘rediscovery’ of descriptions from long ago. The earliestdescription of an association of certain metabolic abnormali-ties, namely hyperlipidemia, obesity, bleeding tendency andsaturated fat ingestion, as well as its successful dietary treat-ment, dates back to the 17th century (3). In the 19th century,Mogagni (3) described an association between visceral obesity,hypertension, bladder stones and atherosclerosis. During the1940s and 1950s, Jean Vague (4) published a series of papers

EXPERT VIEWPOINTS

©2006 Pulsus Group Inc. All rights reserved

AYY Cheng, LA Leiter. Metabolic syndrome under fire:

Weighing in on the truth. Can J Cardiol 2006;22(5):379-382.

In the past two decades, the ‘metabolic syndrome’ has raised much

clinical and research interest and remains a controversial topic. The

constellation of commonly coexisting cardiovascular risk factors, now

known as the metabolic syndrome, has had many definitions which

has added to the confusion surrounding the syndrome. Recently, the

controversy has been escalated by a joint statement from the

American Diabetes Association and the European Association for the

Study of Diabetes calling into question the existence and clinical util-

ity of the metabolic syndrome as a discrete clinical entity. Despite the

controversy, there is agreement that the risk factors of abdominal obe-

sity, hypertension, elevated glucose and dyslipidemia commonly coex-

ist in the same patient, and are important to identify when assessing

an individual patient’s risk. Therefore, whether the ‘syndrome’ is a dis-

tinct clinical entity is not important. By definition, a syndrome is a

group of signs or symptoms that commonly group together. It remains

a useful clinical tool to raise awareness among health care profession-

als to look for ‘nontraditional’ cardiovascular risk factors, such as glu-

cose intolerance or elevated waist circumference, in patients with

other components of the syndrome, without negating the importance

of identifying and treating the other ‘traditional’ risk factors not iden-

tified in the syndrome. It also reminds clinicians of the importance of

lifestyle interventions to treat all of the components of the syndrome.

Therefore, the ‘metabolic syndrome’ continues to serve a useful clini-

cal purpose to raise awareness among health care professionals and aid

in identifying high-risk individuals.

Key Words: Cardiovascular risk assessment; Metabolic syndrome

Le syndrome métabolique dans la ligne de mire :Question de poids et de mesure

Depuis une vingtaine d’années, le « syndrome métabolique » suscite

beaucoup d’intérêt dans le milieu clinique comme en recherche et ce sujet

reste controversé. La coexistence fréquente d’une constellation de facteurs

de risque cardiovasculaires, généralement désignée par le terme syndrome

métabolique, a été définie de plusieurs façons, ce qui a quelque peu

contribué à la confusion qui l’entoure. Or, la controverse a récemment été

ravivée par la position conjointe de l’ American Diabetes Association et de

l’Association européenne pour l’étude du diabète qui remettent en

question la pertinence clinique, voire l’existence du syndrome en tant

qu’entité clinique distincte. Au-delà de la controverse, on s’entend sur le

fait que les facteurs de risque que sont l’obésité abdominale, l’hypertension,

l’hyperglycémie et la dyslipidémie affectent souvent simultanément

certains patients et que ce sont d’importants indicateurs de la nécessité

d’évaluer le risque individuel global. Il devient ainsi secondaire de savoir si

le syndrome est ou non une entité clinique distincte. Un syndrome est

essentiellement un ensemble de signes ou symptômes regroupés. Cette

notion reste utile sur le plan clinique pour éveiller les soupçons des

professionnels de la santé vis-à-vis de certains facteurs de risque non

traditionnels à surveiller, comme l’intolérance au glucose et le tour de

taille excessif chez des patients qui présentent déjà d’autres éléments du

syndrome, sans pour autant nier l’importance du dépistage et de la prise encharge des autres facteurs de risques « traditionnels », moins couramment

liés au syndrome. La notion rappelle en outre aux cliniciens l’importance

des interventions non pharmacologiques pour en traiter tous les éléments.

Par conséquent, le terme « syndrome métabolique » reste pertinent comme

outil clinique pour attirer l’attention des professionnels de la santé et pour

identifier les sujets à risque.



Cheng and Leiter

Can J Cardiol Vol 22 No 5 April 2006380

relating the importance of body fat distribution to the risk of both CVD and DM. In 1965, at the first meeting of the EASD,Avogaro et al (5) presented the first systematic description of asyndrome involving hyperlipidemia, obesity, DM, ischemicheart disease and arterial hypertension. Then, in 1988, Reaven(6) introduced what he termed ‘syndrome X’ in his BantingLecture at the ADA meeting. This was described as a clusteringof disturbances in glucose and insulin metabolism, dyslipidemiaand hypertension with insulin resistance/hyperinsulinemia as acritical underlying factor representing an important cardiovas-cular risk factor. This clustering was subsequently called the‘insulin resistance syndrome’ and even ‘Reaven’s syndrome’.‘Metabolic syndrome’ is the currently accepted term, and themost widely used clinical criteria come from the World HealthOrganization (WHO) (Table 1) (7), the Third Report of the

National Cholesterol Education Program Adult TreatmentPanel III (NCEP ATP III) (Table 2) (1,8) and, most recently,the International Diabetes Federation (IDF) (Table 3) (9,10).

CLINICAL CRITERIA FOR THE METABOLICSYNDROME

WHO (1998)A consultation group was organized by the WHO in 1998 to

describe and define the metabolic syndrome (7). The primary

consequence of the metabolic syndrome is CVD. Insulin resist-ance (IR) was felt to be the most important underlying factorand, therefore, a necessary component of the syndrome. IR wasdefined as the presence of type II DM, impaired fasting glucose(IFG), impaired glucose tolerance (IGT) or lowered insulinsensitivity measured under hyperinsulinemic and euglycemicconditions. In addition to IR, at least two other componentswere needed to diagnose metabolic syndrome (hypertension,obesity [measured by body mass index or waist-to-hip ratio],hypertriglyceridemia, low high density lipoprotein [HDL] ormicroalbuminuria). Other identified parts of the metabolicsyndrome included hyperuricemia, hypercoagulability and

hyperleptinemia, but these were not required.

NCEP ATP III (2001)The NCEP ATP III report also recognized the metabolic syn-drome as a major risk factor for CVD (1) but the precise clini-cal criteria differed from those of the WHO. Six componentswere described that related to CVD: abdominal obesity;atherogenic dyslipidemia; raised blood pressure; IR with orwithout glucose intolerance; proinflammatory state; and pro-thrombotic state. Obesity, abnormal fat distribution, IR andother factors (age, genetics and hormonal changes) were dis-cussed as possible players in the pathogenesis of metabolic syn-drome, but no definite conclusions were drawn. The actualclinical criteria are shown in Table 2. At least three of the fivelisted characteristics were required. These characteristicsincluded abdominal obesity measured by waist circumference,hypertension, hypertriglyceridemia, low HDL and raised plasmaglucose. The presence of type II DM did not exclude the diag-nosis of metabolic syndrome. This definition differed from theWHO definition in that IR was not a necessary component,although the assumption was made that the vast majority of patients who met the criteria would have IR. Also, a glucosetolerance test or 2 h postprandial glucose value was perceivedto be clinically impractical. Thus, an abnormality in the fast-ing glucose level was felt to be sufficient to demonstrate glu-cose intolerance. Most recently, the fasting glucose thresholdwas modified and reduced to 5.6 mmol/L to reflect the modi-

fied definition of IFG proposed by the ADA (8).

TABLE 1World Health Organization clinical criteria for themetabolic syndrome

Insulin resistance, defined by one of the following:

• Type II diabetes mellitus

• Impaired fasting glucose (fasting plasma glucose of 6.1 mmol/L or greater)

• Impaired glucose tolerance (2 h postprandial glucose of 7.8 mmol/L or greater)

• Glucose uptake below the lowest quartile for background population under

investigation under hyperinsulinemic, euglycemic conditions (for those with normal fasting glucose levels)

Plus two of the following:

• High blood pressure (systolic 140 mmHg or higher, or diastolic 90 mmHg

or higher) and/or antihypertensive medication

• Plasma triglyceride concentration of 1.7 mmol/L or higher

• High-density lipoprotein cholesterol less than 0.9 mmol/L in men or less

than 1.0 mmol/L in women

• Body mass index greater than 30 kg/m2 and/or waist to hip ratio greater

than 0.9 in men or greater than 0.85 in women

• Urinary albumin excretion rate of 20 µg/min or greater, or albumin to

creatinine ratio of 30 mg/g or greater

Adapted from reference 7

TABLE 2National Cholesterol Education Program Adult TreatmentPanel III clinical criteria for identification of the metabolicsyndrome

Three or more of the following:

• Abdominal obesity (waist circumference measurement)

Men: greater than 102 cm

Women: greater than 88 cm

• Triglyceride concentration of 1.7 mmol/L or higher

• High-density lipoprotein cholesterol concentration

Men: less than 1.03 mmol/L

Women: less than 1.30 mmol/L

• Blood pressure 130/85 mmHg or higher

• Fasting glucose of 5.6 mmol/L or higher

Adapted from references 1 and 8

TABLE 3International Diabetes Federation consensus definition of the metabolic syndrome

Definition of metabolic syndrome

Central adiposity (waist circumference, cm) Men Women

Europid* ≥94 ≥80

South Asian†≥90 ≥80

Chinese ≥90 ≥80

Japanese ≥85 ≥90

Plus any two of the following:

Triglyceride concentration of 1.7 mmol/L or higher

High-density lipoprotein less than 0.9 mmol/L for men, or less than

1.1 mmol/L for women

Blood pressure (systolic 130 mmHg or greater, or diastolic 85 mmHg or

greater) or antihypertensive treatment

Fasting plasma glucose of 5.6 mmol/L or greater, or pre-existing diabetes,

or impaired glucose tolerance

*Europid criteria for individuals of European, sub-Saharan African or MiddleEastern descent; † South Asian criteria for individuals of South Asian, South or Central American descent. Adapted from references 3 and 4



IDF consensus (2005)As of 2004, there were at least four different sets of publishedcriteria for the metabolic syndrome. Given the lack of univer-sally accepted criteria, the IDF convened an internationalgroup in May 2004 to establish yet another working diagnostictool for the metabolic syndrome that could identify individualsat high risk of developing CVD and DM. In April 2005, theconsensus definition was presented in Berlin at the First

International Congress on ‘Prediabetes’ and the MetabolicSyndrome – Epidemiology, Management and Prevention of Diabetes and Cardiovascular Disease (9,10) (Table 3). The keycomponents were central adiposity, dyslipidemia, hypertensionand dysglycemia.

‘Central adiposity’, assessed clinically by an increased waistcircumference, was determined to be an absolute necessity forthe syndrome due to its strong correlation with the other fea-tures of the metabolic syndrome and its probable role in thepathogenesis of the metabolic abnormalities. Previous criteriafor the metabolic syndrome suggested waist circumferencethresholds for men and women that were supposed to beapplied universally, regardless of ethnicity. However, it was evi-

dent that metabolic abnormalities were present in individualsof certain ethnicities at much lower waist circumferences (11).Thus, the IDF definition proposed ethnicity-specific waist cir-cumference values, identifying four major ethnic groupingsbased on best available data: Europid (defined in Table 3),South Asian, Chinese and Japanese.

In addition to central adiposity, individuals required two ormore of the following: hypertriglyceridemia, low HDL,increased blood pressure and glucose intolerance (IFG, IGT orDM). Unlike the WHO definition, IR was not specificallyidentified because it was felt that central obesity plus hyper-triglyceridemia were sufficiently adequate surrogates for IR.

THE CONTROVERSYIn September 2005, the ADA and EASD published a jointstatement calling into question the existence of metabolic syn-drome, as defined by the NCEP and the WHO, as a clinicalentity based on their interpretation of the available evidence(2). A number of concerns were raised regarding the currentdescriptions of the syndrome. These concerns includedambiguous criteria with ill-defined threshold values; question-able value of including DM in the definition because DM isalready known to be a very significant risk factor for CVD;uncertainty of IR as the unifying etiology; lack of basis forincluding or excluding other CVD risk factors; variability of CVD risk dependent on the specific risk factor present; noadditional CVD risk associated with the ‘metabolic syndrome’compared with the sum of its parts; no difference betweentreatment of the ‘syndrome’ and the treatment of the individ-ual components; and unclear medical value of diagnosing the‘syndrome’. Therefore, the ADA and EASD concluded thatclinicians should no longer rely on, or look for, the presenceof the ‘metabolic syndrome’ as a clinical entity and shouldconcentrate their efforts on identifying and treating the indi-vidual CVD risk factors. This statement added to the existingconfusion regarding the metabolic syndrome, previously gener-ated by the multiple clinical criteria, and somewhat inconsis-tent study results and incompatibility of studies. Within amonth of the publication of this statement, the AmericanHeart Association (AHA) and the National Heart, Lung, and

Blood Institute (NHLBI) published a joint statement supporting

the existence of the metabolic syndrome and the NCEP ATPIII definition (8), and the IDF also published their summary of the consensus criteria and support for the existence of themetabolic syndrome as an important clinical entity (10).

INTERPRETATIONThe ADA/EASD joint statement, AHA/NHLBI joint state-ment and IDF publication were all published within one

month of each other in four different European and NorthAmerican high-impact scientific journals. This obviouslyregenerated a lot of attention focusing on the existence andclinical importance of the metabolic syndrome. Interestingly,what has often been ignored in the ‘controversy’ is that thestatements from the various organizations agreed with eachother more than they differed.

The ADA/EASD statement suggests that the metabolicsyndrome should not be considered a clinical entity becausethe underlying etiology is unknown and the criteria are impre-cise. This point is actually acknowledged by the other organi-zations. The AHA, NHLBI and IDF agree that the metabolicsyndrome should not be considered a discrete clinical entity

and acknowledge that the underlying etiology is unclear. Asyndrome, as defined by the Oxford English Dictionary, is ‘agroup of symptoms or signs that consistently occur together’(12). Based on this definition, the current definitions of meta-bolic syndrome qualify as a ‘syndrome’. All of the groups basi-cally acknowledge that the various components of themetabolic syndrome often do occur in the same patient.Furthermore, it is important to note that the various publishedcriteria (WHO, NCEP, IDF, etc) are all consistent in their def-inition of the syndrome in that they all agree on a conceptualdefinition that includes an atherogenic dyslipidemia, IR/glucoseintolerance, a proinflammatory and prothrombotic profile, andraised blood pressure. The differences in opinion between the

groups are related to the clinical criteria used to identifypatients with the syndrome. It is certainly true that many of the criteria are imprecise, a fact acknowledged by the variousorganizations. Over the years, a number of studies have beenperformed regarding the prevalence of the metabolic syndromeand its associated cardiovascular risk; however, the existence of multiple clinical criteria has made it difficult to compare stud-ies and, therefore, precise thresholds have not been estab-lished. Many of the proposed thresholds are based on bestavailable evidence or, in some cases, are arbitrary. However,this may be a necessary intermediate step to improve ease of clinical utility and, more importantly, to create a frameworkfrom which future research can be performed in an attempt toverify or redefine the thresholds. None of the existing defini-tions claim to be perfect, precise or definitive. As with manydiagnostic criteria in medicine, they will continue to be subjectto change and redefinition.

Finally, and perhaps most importantly, the clinical utility of the metabolic syndrome was also called into question. Themain purpose of identifying the metabolic syndrome is to helpphysicians, and especially those in primary care, to identifypatients at high risk of developing CVD or DM. All of thegroups acknowledge that each component of the metabolicsyndrome represents a significant risk factor. However, itremains controversial as to whether the ‘syndrome’ itself repre-sents a higher cardiovascular risk than the sum of the risk fac-tors themselves. Although this is certainly an important

research question, it may not be a useful clinical distinction. If

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REFERENCES1. National Cholesterol Education Program (NCEP) Expert Panel on

Detection, Evaluation, and Treatment of High Blood Cholesterolin Adults (Adult Treatment Panel III). Third report of the

National Cholesterol Education Program (NCEP) expert panel ondetection, evaluation, and treatment of high blood cholesterol inadults (Adult Treatment Panel III) final report. Circulation2002;106:3143-421.

2. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome:Time for a critical appraisal: Joint statement from the AmericanDiabetes Association and the European Association for the Study of Diabetes. Diabetologia 2005;48:1684-99.

3. Erkelens DW, de Bruin TW, Castro Cabezas M. Tulp syndrome.Lancet 1993;342:1536-7.

4. Vague J. The degree of masculine differentiation of obesities:A factor determining predisposition to diabetes, atherosclerosis,gout, and uric calculous disease. Am J Clin Nutr 1956;4:20-34.

5. Avogaro P, Crepaldi G, Enzi G, Tiengo A. [Association of

hyperlipidemia, diabetes mellitus and mild obesity.]Acta Diabetol Lat 1967;4:572-90.

6. Reaven GM. Banting lecture 1988. Role of insulin resistance inhuman disease. Diabetes 1988;37:1595-607.

7. World Health Organization. Definition, Diagnosis and Classification

of Diabetes Mellitus and its Complications. Report of a WHOConsultation. Part 1: Diagnosis and Classification of DiabetesMellitus. Geneva: World Health Organization, 1999.<http://whqlibdoc.who.int/hq/1999/WHO_NCD_NCS_99.2.pdf>(Version current at March 3, 2006).

8. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis andmanagement of the metabolic syndrome: An American HeartAssociation/National Heart, Lung, and Blood Institute scientificstatement. Circulation 2005;112:2735-52.

9. International Diabetes Federation. The IDF consensus worldwidedefinition of the metabolic syndrome.<http://www.idf.org/webdata/docs/MetSyndrome_FINAL.pdf>(Version current at March 3, 2006).

10. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome – a newworldwide definition. Lancet 2005;366:1059-62.

11. WHO Expert Consultation. Appropriate body-mass index for Asian

populations and its implications for policy and interventionstrategies. Lancet 2004;363:157-63. (Erratum in 2004;363:902).

12. Soares C, Hawker S, eds. Compact Oxford English Dictionary of Current English, 3rd edn. Oxford: Oxford University Press, 2005.

one has more risk factors, one is at higher CVD risk. Currentrisk engines, such as the Framingham risk score, have issues of their own and high-risk patients are often missed because of their failure to incorporate both newer (eg, visceral fat, inflam-mation) as well as traditional (eg, family history of prematureCVD) risk factors. Furthermore, most physicians do not rou-tinely use such risk engines. Therefore, if the identification of a ‘syndrome’ helps clinicians to recognize a high-risk patient

and remember to assess nonclassical CVD risk factors, such asIFG or IGT or elevated waist circumference, and then instituteappropriate therapies (often lifestyle) targeting these risk fac-tors, then the definition has served its clinical utility. The exis-tence of the syndrome does not preclude the search for theother classical CVD risk factors, such as smoking and familyhistory. These other risk factors remain important componentsof the assessment for a patient’s overall CVD risk. Perhaps theclinical utility of the metabolic syndrome definition is its abilityto raise awareness among clinicians to identify nontraditionalrisk factors for CVD that also warrant therapy, and not whetherit can identify at-risk patients better than existing models.

The definition of the metabolic syndrome has served

another important clinical purpose. It has raised awareness of the differences in cardiovascular risk factors in various ethnicpopulations and has sparked research into this important issue.When the initial definitions were applied to various popula-tions around the world, it was discovered that they oftenunderestimated CVD risk. Therefore, ethnicity-specific defini-tions have been proposed by the IDF. In addition to these ethnicdifferences, the identification and definition of the metabolicsyndrome has generated a number of research hypothesesabout its validity, predictive abilities and perhaps most impor-tantly, its underlying etiologies. In that sense, the metabolic

syndrome as a clinical entity has served, and will likely continueto serve for many years, another important purpose.

CONCLUSIONSSince Reaven’s Banting lecture identifying the common clus-tering of CVD risk factors in the same patient and his proposalof an underlying etiology, there has been, and continues to be,much research and clinical interest in the metabolic syndrome.

The multiple definitions and incompatibility of studies per-formed to date has generated much confusion. A recent jointstatement from the ADA/EASD has generated even more con-troversy. However, despite the confusion, the metabolic syn-drome still plays an important role in patient assessment.The clustering of CVD risk factors qualifies it as a syndrome.The existence of the components increases one’s CVD risk.The metabolic syndrome has raised awareness among healthcare professionals to identify and initiate therapy for ‘nontradi-tional’ CVD risk factors, without negating the importance of identifying and treating the other traditional risk factors (eg,smoking, age, sex and family history). It has also raised ques-tions about ethnic differences that had long been neglected.

Therefore, if the identification of a ‘syndrome’ helps cliniciansto recognize a high-risk patient and remember to assess non-classical CVD risk factors, such as IFG, IGT or elevated waistcircumference, then the definition has served its clinical utility.In addition, the ‘syndrome’ emphasizes the commonality of thevarious components, including their uniform response tolifestyle interventions of weight loss and physical activity,thereby further stressing the importance of lifestyle interven-tions. Therefore, the metabolic syndrome is an important clin-ical syndrome and should continue to be considered byclinicians and researchers.

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Metabolic Syndrome Under Fire